Title

Author

Defense Date

2008

Document Type

Thesis

Degree Name

Master of Science

Department

Physiology

First Advisor

Roland N. Pittman

Abstract

Hemoglobin-based oxygen carriers (HBOCs) offer a safe, more plentiful and long term alternate to blood banks. However, they have been found to increase blood pressure which can be attributed to an increase in total peripheral resistance (TPR). Lumenal nitric oxide (NO) scavenging by these HBOCs seems to be responsible for this hypertensive effect. In addition, it is believed that hemoglobin (Hb) tetramers and dimers may extravasate and consume additional nitric oxide in the perivascular and interstitial space. The purpose of the present study was to elucidate the role of NO scavenging and to confirm extravasation as a contributor to HBOC vasopressor effects in the spinotrapezius muscle. The present study investigated the vessel reactivity and mean arterial pressure response to three HBOCs: HBOC 201, HBOC 205 MW 400, and HBOC 205 MW 600. These varied in molecular weight (MW) and percentage of tetramers and dimers. It was found that larger polymers of HBOC showed no significant decrease in vasoactivity. Although larger polymers are less likely to extravasate, the remaining tetramers and dimers seem sufficient to contribute to the observed vasoactivity. Using NaNO2, a NO donor, in conjunction with the HBOCs almost completely abolished this hypertensive effect at higher concentrations. Further examination utilizing a nitric oxide synthase (NOS) inhibitor to mimic the HBOC vasopressor effects demonstrated that lower concentrations of NaNO2 were able to abolish the hypertensive effect. In vitro studies only further supported these results by demonstrating that NO consumption increases with HBOC dose. HBOC labeled with TRITC showed conclusive evidence that extravasation also plays a role in NO scavenging, even when minimal amounts of tetramers and dimers are present. In conclusion, the present study offers strong evidence that NO scavenging is responsible for the observed vasopressor effects. It also offers evidence supporting the theory that HBOC extravasation may be contributing to these vasopressor effects as well.